Pharmacological characterization of [D-Ala2,Leu5,Ser6]enkephalin (DALES): antinociceptive actions at the δnon-complexed-opioid receptor

Antonia Mattia, Todd Vanderah, Henry I. Mosberg, John R. Omnaas, Wayne D. Bowen, Frank Porreca

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Substantial evidence has been accumulated which suggests that opioid δ receptors may be distinguished on the basis of their involvement in the modulation (i.e., increase or decrease in potency) of μ-mediated antinociception. On this basis, it has been hypothesized that some opioid δ receptors exist within a functional complex with μ receptors (δcomplexedcx) receptors) while other δ sites do not (δnon-complexedncx) receptors). Recent work with [D-Ala2,Leu5,Cys6]enkephalin (DALCE) has demonstrated that this compound produces initial antinociceptive actions, does not modulate morphine antinociception and appears to bind irreversibly to the δncx site, presumably by means of thiol-disulfide exchange between the receptor and the cysteine sulfhydryl group. To determine if a structural basis exists for actions at the hypothesized δncx receptor, in the present study we report the synthesis and pharmacological characterization of [D-Ala2,Leu5,Ser6]enkephalin (DALES), a close structural analogue of DALCE. If a structural basis for action at the δncx site exists, then DALES would be predicted to produce antinociception, fail to modulate morphine antinociception and, since it lacks the free sulfhydryl group present in DALCE, fail to exhibit irreversible antagonistic actions; these predictions were supported. Additionally, pretreatment with DALCE at - 24 h, but not with DALES, blocked DALES-induced antinociception. These observations in vivo support the concept of a structural basis for activity at the hypothesized δncx site and suggest that DALES, like DALCE, may be a useful probe for pharmacological characterization of putative δ receptor subtypes.

Original languageEnglish (US)
Pages (from-to)371-375
Number of pages5
JournalEuropean Journal of Pharmacology
Volume192
Issue number3
DOIs
StatePublished - Jan 17 1991

Fingerprint

Enkephalins
Opioid Receptors
Pharmacology
Morphine
Sulfhydryl Compounds
Disulfides
Cysteine

Keywords

  • (Intracerebroventricular)
  • DALES ([D-Ala,Leu,Ser]enkephalin)
  • Enkephalins
  • Opioid antinociception
  • δ-Opioid receptors
  • μ-Opioid receptors

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Pharmacological characterization of [D-Ala2,Leu5,Ser6]enkephalin (DALES) : antinociceptive actions at the δnon-complexed-opioid receptor. / Mattia, Antonia; Vanderah, Todd; Mosberg, Henry I.; Omnaas, John R.; Bowen, Wayne D.; Porreca, Frank.

In: European Journal of Pharmacology, Vol. 192, No. 3, 17.01.1991, p. 371-375.

Research output: Contribution to journalArticle

@article{239f20d557c04cdaacdaa58db0b9e6a5,
title = "Pharmacological characterization of [D-Ala2,Leu5,Ser6]enkephalin (DALES): antinociceptive actions at the δnon-complexed-opioid receptor",
abstract = "Substantial evidence has been accumulated which suggests that opioid δ receptors may be distinguished on the basis of their involvement in the modulation (i.e., increase or decrease in potency) of μ-mediated antinociception. On this basis, it has been hypothesized that some opioid δ receptors exist within a functional complex with μ receptors (δcomplexed (δcx) receptors) while other δ sites do not (δnon-complexed (δncx) receptors). Recent work with [D-Ala2,Leu5,Cys6]enkephalin (DALCE) has demonstrated that this compound produces initial antinociceptive actions, does not modulate morphine antinociception and appears to bind irreversibly to the δncx site, presumably by means of thiol-disulfide exchange between the receptor and the cysteine sulfhydryl group. To determine if a structural basis exists for actions at the hypothesized δncx receptor, in the present study we report the synthesis and pharmacological characterization of [D-Ala2,Leu5,Ser6]enkephalin (DALES), a close structural analogue of DALCE. If a structural basis for action at the δncx site exists, then DALES would be predicted to produce antinociception, fail to modulate morphine antinociception and, since it lacks the free sulfhydryl group present in DALCE, fail to exhibit irreversible antagonistic actions; these predictions were supported. Additionally, pretreatment with DALCE at - 24 h, but not with DALES, blocked DALES-induced antinociception. These observations in vivo support the concept of a structural basis for activity at the hypothesized δncx site and suggest that DALES, like DALCE, may be a useful probe for pharmacological characterization of putative δ receptor subtypes.",
keywords = "(Intracerebroventricular), DALES ([D-Ala,Leu,Ser]enkephalin), Enkephalins, Opioid antinociception, δ-Opioid receptors, μ-Opioid receptors",
author = "Antonia Mattia and Todd Vanderah and Mosberg, {Henry I.} and Omnaas, {John R.} and Bowen, {Wayne D.} and Frank Porreca",
year = "1991",
month = "1",
day = "17",
doi = "10.1016/0014-2999(91)90227-H",
language = "English (US)",
volume = "192",
pages = "371--375",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",
number = "3",

}

TY - JOUR

T1 - Pharmacological characterization of [D-Ala2,Leu5,Ser6]enkephalin (DALES)

T2 - antinociceptive actions at the δnon-complexed-opioid receptor

AU - Mattia, Antonia

AU - Vanderah, Todd

AU - Mosberg, Henry I.

AU - Omnaas, John R.

AU - Bowen, Wayne D.

AU - Porreca, Frank

PY - 1991/1/17

Y1 - 1991/1/17

N2 - Substantial evidence has been accumulated which suggests that opioid δ receptors may be distinguished on the basis of their involvement in the modulation (i.e., increase or decrease in potency) of μ-mediated antinociception. On this basis, it has been hypothesized that some opioid δ receptors exist within a functional complex with μ receptors (δcomplexed (δcx) receptors) while other δ sites do not (δnon-complexed (δncx) receptors). Recent work with [D-Ala2,Leu5,Cys6]enkephalin (DALCE) has demonstrated that this compound produces initial antinociceptive actions, does not modulate morphine antinociception and appears to bind irreversibly to the δncx site, presumably by means of thiol-disulfide exchange between the receptor and the cysteine sulfhydryl group. To determine if a structural basis exists for actions at the hypothesized δncx receptor, in the present study we report the synthesis and pharmacological characterization of [D-Ala2,Leu5,Ser6]enkephalin (DALES), a close structural analogue of DALCE. If a structural basis for action at the δncx site exists, then DALES would be predicted to produce antinociception, fail to modulate morphine antinociception and, since it lacks the free sulfhydryl group present in DALCE, fail to exhibit irreversible antagonistic actions; these predictions were supported. Additionally, pretreatment with DALCE at - 24 h, but not with DALES, blocked DALES-induced antinociception. These observations in vivo support the concept of a structural basis for activity at the hypothesized δncx site and suggest that DALES, like DALCE, may be a useful probe for pharmacological characterization of putative δ receptor subtypes.

AB - Substantial evidence has been accumulated which suggests that opioid δ receptors may be distinguished on the basis of their involvement in the modulation (i.e., increase or decrease in potency) of μ-mediated antinociception. On this basis, it has been hypothesized that some opioid δ receptors exist within a functional complex with μ receptors (δcomplexed (δcx) receptors) while other δ sites do not (δnon-complexed (δncx) receptors). Recent work with [D-Ala2,Leu5,Cys6]enkephalin (DALCE) has demonstrated that this compound produces initial antinociceptive actions, does not modulate morphine antinociception and appears to bind irreversibly to the δncx site, presumably by means of thiol-disulfide exchange between the receptor and the cysteine sulfhydryl group. To determine if a structural basis exists for actions at the hypothesized δncx receptor, in the present study we report the synthesis and pharmacological characterization of [D-Ala2,Leu5,Ser6]enkephalin (DALES), a close structural analogue of DALCE. If a structural basis for action at the δncx site exists, then DALES would be predicted to produce antinociception, fail to modulate morphine antinociception and, since it lacks the free sulfhydryl group present in DALCE, fail to exhibit irreversible antagonistic actions; these predictions were supported. Additionally, pretreatment with DALCE at - 24 h, but not with DALES, blocked DALES-induced antinociception. These observations in vivo support the concept of a structural basis for activity at the hypothesized δncx site and suggest that DALES, like DALCE, may be a useful probe for pharmacological characterization of putative δ receptor subtypes.

KW - (Intracerebroventricular)

KW - DALES ([D-Ala,Leu,Ser]enkephalin)

KW - Enkephalins

KW - Opioid antinociception

KW - δ-Opioid receptors

KW - μ-Opioid receptors

UR - http://www.scopus.com/inward/record.url?scp=0025978570&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025978570&partnerID=8YFLogxK

U2 - 10.1016/0014-2999(91)90227-H

DO - 10.1016/0014-2999(91)90227-H

M3 - Article

C2 - 1647317

AN - SCOPUS:0025978570

VL - 192

SP - 371

EP - 375

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 3

ER -